This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is the main research project in our laboratory where regulation of CART gene expression has been a focus. We previously showed that over expression of CREB in the N Acc increased expression of CART peptide and we found that CREB is an in vivo regulator of CART expression which appears to be a mechanism of the action of cocaine. CART peptide acts as a homeostatic regulator and tends to oppose the action of cocaine in the nucleus accumbens. In the past period, we have shown using ChIP assays that CREB and P-CREB bind to the region of the CART promoter that contains the CRE site, suggesting a direct effect of CREB on the CART gene. Additional work supported has been the identification of siRNAs that reduce CART peptide levels after in vivo injection. Several siRNAs have been found that, in preliminary experiments, reduce CART peptide levels. This is important because until now there has been no way to acutely and abruptly reduce CART peptide levels in brain regions. Useful behavioral studies can be carried out if CART peptide levels can be acutely reduced.